Estrogen Sensitivity and Ovulatory Dysfunction in Obesity

April 2, 2015 updated by: University of Colorado, Denver

The sole purpose of this study is to evaluate pathophysiology of disease. The disease state that is being evaluated is the obesity-related alterations in reproductive hormones

  • The obesity epidemic in the United States is advancing at an accelerated pace. It is estimated that by 2015, 41% of U.S. adults will be obese as defined by a body mass index (BMI) of greater than 30 kg/m2. The U.S. government's 2010 Dietary Guidelines regard obesity as the single greatest health hazard in this century. Female adult obesity is associated with menstrual cycle irregularities, ovulatory dysfunction and a higher risk of obstetrical complications. This reproductive phenotype of obesity is worsened by further increases in BMI and is not solely due to anovulatory infertility. While the association of adiposity with subfertility is well documented in population studies, the underlying mechanisms remain poorly understood. The main objective of this proposal is to clarify the nature of the obesity-related reproductive endocrine abnormalities and identify potential etiologies amenable to therapy.
  • Hypothesis: The hypothalamic-pituitary axis is abnormally sensitive to estradiol negative feedback in obesity.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

  • Design: paired assessments Pre and Post estrogen administration in obese and normal weight women
  • AIM 1: To test the pituitary and hypothalamic responsiveness in obesity, we will examine the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) pulsatility during frequent blood sampling.
  • AIM 2: To test the ovarian responsiveness in obesity, we will examine urinary reproductive hormones (E1c, estrone conjugates, and Pdg, pregnanediol glucuronide) over an entire menstrual cycle.
  • AIM 3: To test the hypothesis that central adiposity is associated with reproductive hormone alterations in obesity, we will quantitatively assess body composition by dual energy x-ray absorptiometry (DXA).

Study Type

Interventional

Enrollment (Actual)

30

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Colorado
      • Aurora, Colorado, United States, 80045
        • University of Colorado, Anschutz Medical Campus

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years to 38 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • Age 18-42 at study entry
  • Regular menstrual cycles every 25-40 days
  • BMI 18- 25 kg/m2 or ≥30kg/m2
  • Good general health
  • Prolactin and thyroid-stimulating hormone (TSH) within normal laboratory ranges at screening
  • Baseline hemoglobin >11 gm/dl.

Exclusion Criteria:

  • Positive screen for Activated Protein C resistance
  • Any contraindications to exogenous estrogen, including previous thromboembolic events or stroke, history of an estrogen-dependent tumor, active liver disease, undiagnosed abnormal uterine bleeding, hypertriglyceridemia, smoking, hypertension
  • History of chronic disease affecting hormone production, metabolism or clearance (including diabetes mellitus) or abnormal renal or liver function at screening, such as elevated aspartate or alanine aminotransferases or elevated blood urea nitrogen (BUN) or creatinine
  • Current use of thiazolidinediones or metformin (known to interact with reproductive hormones)
  • Use of hormones affecting hypothalamic-pituitary ovarian axis within three months of enrollment
  • Strenuous exercise (>4 hours per week)
  • Pregnancy, breast-feeding or current active attempts to conceive

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Group 1 - Normal Weight

Group 1: Normal weight (BMI 18-25 kg/m2)

Subjects were instructed to apply 0.1 mg/d transdermal estrogen (Estradiol) for one month. Pituitary response was assessed to determine how estradiol administration altered pituitary sensitivity to Gonadotropin-releasing hormone - GnRH. Subjects who failed to initiate a menstrual period following 40 days on the patch were instructed to take 200 mg daily of progesterone for 10 days or as long as deemed necessary.
Drug: Estradiol
Subjects were instructed to apply 0.1 mg/d transdermal estrogen for one month.
Other Names:
  • Climara, transdermal estrogen
Drug: Gonadotropin-releasing hormone (GnRH)
Pituitary response was assessed to determine how estradiol administration alters pituitary sensitivity to GnRH.
Other Names:
  • Lutrelef or gonadorelin acetate
Drug: Progesterone
Subjects who failed to initiate a menstrual period following 40 days on the patch were instructed to take 200 mg daily of progesterone for 10 days or as long as deemed necessary.
Other Names:
  • Prometrium or medroxyproge sterone acetate
Experimental: Group 2 - Obese

Group 2: Obese (BMI >30 kg/m2)

Subjects were instructed to apply 0.1 mg/d transdermal estrogen (Estradiol) for one month. Pituitary response was assessed to determine how estradiol administration altered pituitary sensitivity to Gonadotropin-releasing hormone - GnRH. Subjects who failed to initiate a menstrual period following 40 days on the patch were instructed to take 200 mg daily of progesterone for 10 days or as long as deemed necessary.
Drug: Estradiol
Subjects were instructed to apply 0.1 mg/d transdermal estrogen for one month.
Other Names:
  • Climara, transdermal estrogen
Drug: Gonadotropin-releasing hormone (GnRH)
Pituitary response was assessed to determine how estradiol administration alters pituitary sensitivity to GnRH.
Other Names:
  • Lutrelef or gonadorelin acetate
Drug: Progesterone
Subjects who failed to initiate a menstrual period following 40 days on the patch were instructed to take 200 mg daily of progesterone for 10 days or as long as deemed necessary.
Other Names:
  • Prometrium or medroxyproge sterone acetate

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Luteinizing Hormone Pulse Amplitude
Time Frame: Baseline
The study is powered on luteinizing hormone pulse amplitude because it is the clinical outcome for which the most data is available. The primary comparison is whether there is a significant reduction in the pulse amplitude in the obese between the pre- and post-treatment periods and whether there is no change in the pulse amplitude in the normal weight patients between the pre and post-treatment periods.
Baseline
Luteinizing Hormone Pulse Amplitude
Time Frame: Post estradiol at one month
Post estradiol at one month

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Colorado, Denver

Investigators

  • Principal Investigator: Alex Polotsky, MD, University of Colorado, Denver

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2011

Primary Completion (Actual)

January 1, 2013

Study Completion (Actual)

January 1, 2013

Study Registration Dates

First Submitted

June 22, 2011

First Submitted That Met QC Criteria

June 22, 2011

First Posted (Estimate)

June 27, 2011

Study Record Updates

Last Update Posted (Estimate)

April 20, 2015

Last Update Submitted That Met QC Criteria

April 2, 2015

Last Verified

April 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 11-0293

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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